In this project we will critically examine two biomarkers found to be strongly associated with AD in the previous funding cycle. First, using biological samples and clinical data from the baseline assessment and first follow-up, we will greatly expand our work on plasma Abeta42 and Abeta40 by attempting to replicate our previous findings in a much larger and more extensive longitudinal study focusing on the outcomes: AD and MCI. We will have to opportunity to investigate how and when Abeta42 and Abeta40 plasma levels changes during the transition from healthy (without dementia) to MCI and then to AD, and to investigate variation in plasma levels by age, ethnic group, APOE genotype, use of antiinflammatory drugs and in relation to other putative clinical risk factors. We will investigate the relation between Abeta42 and Abeta40 in plasma and autoantibody production to AlL Second, we will broaden our preliminary work on a second biomarker: structural and functional MRI. Initially, we will compare the basal metabolism in the entorhinal cortex, dentate and CAt subregions of the hippocampus and the volume of the hippocampus in healthy elderly and those with individuals who have MCI using a cross-sectional approach. We will then examine the association between APOE-epsilon4 and variation in the TP73 gene in relation to the size and basal metabolism within the hippocampus and its subregions. We will also use the acquired imaging data to examine their association between clinical risk factors for AD. Most importantly, we will use the imaging data acquired at the second follow-up to examine the subsequent risk of MCI and AD and in relation to the basal metabolism within the hippocampus and its subregions and hippocampal volume using a longitudinal approach. Further, we will examine the change in memory and other cognitive function over time in relation to the basal metabolism within the hippocampus and hippocampal volume. The underlying premise of this investigation is that as elderly individuals progress from normal cognitive function through MCI to AD, there is a parallel sequence occurring in the hippocampus. A decrease in basal metabolism precedes the shift from normal cognitive function to MCI followed by hippocampal atrophy, which precedes the transition from MCI to AD. It is our intent to characterize the relation between these antecedent biomarkers and both clinical and genetic risk factors for MCI and AD. With our first follow-up completed and our second, third and fourth anticipated we feel we are in an excellent position to broaden this prospective investigation of elderly African-Americans, Hispanics and Caucasians, which provides a unique opportunity to understand mechanisms related to the disease risk.